Steven C. Schachter MD
Associate Professor, Department of Neurology, Harvard Medical School; and Director of Clinical Trials, Beth Israel Deaconess Medical Center, Boston, Massachusetts
The available treatments for seizures dramatically increased during the 1990s—the decade of the brain. Although the chemical structures of most new antiepileptic drugs (AEDs) are distinctly different from available therapies, others share structural similarities. Two drugs that are similar in structure may have identical actions, such as fosphenytoin and phenytoin (PHT). Alternatively, two structurally similar drugs may have different metabolic pathways, and therefore potentially different clinical profiles.
Carbamazepine (CBZ) is a first-line drug for partial seizures (1); however, its use is limited in some patients by toxicity or ineffectiveness. Oxcarbazepine (OXC), a 10-keto analog of CBZ, is primarily metabolized by reduction, whereas CBZ undergoes oxidation to the 10, 11-CBZ epoxide, as discussed in Chapter 45. The epoxide probably accounts for some of the toxicity associated with CBZ (2).
This chapter reviews the efficacy and clinical status of OXC for the treatment of seizures.
Five studies compared the efficacy of OXC as monotherapy with that of other first-line AEDs (Table 47.1). The first controlled comparative trial of OXC monotherapy enrolled 40 patients with a variety of epilepsy syndromes who had refractory seizures or unwanted side effects on PHT monotherapy (3). Patients were converted from PHT monotherapy to either OXC or CBZ and dosed to clinical effect for 48 to 50 weeks. This double-blind, parallel-group study showed equivalent efficacy for OXC (600 to 900 mg/day) and CBZ (400 to 800 mg/day). Similarly, Dam et al. dosed OXC and CBZ to clinical effect in a parallel-group, double-blind study of 235 patients with newly diagnosed partial-onset or primary generalized seizures and found equivalent efficacy over 48 weeks of treatment (4).
Three other multicenter, randomized, double-blind, parallel-group, monotherapy trials of OXC in patients with newly diagnosed or previously untreated partial-onset or primary generalized seizures have been performed (Table 47.2). One study compared OXC with valproate (VPA) (5) and the other two compared OXC with PHT—one in adults (6) and one in children and adolescents (7). Each of these studies had a retrospective baseline period; patients had to have at least two seizures separated by more than 48 hours in the preceding 6 months to qualify. Randomization was 1:1. Blinded treatment was administered three times daily and titrated over 8 weeks based on clinical response.
In the OXC versus VPA study, randomized patients were titrated to between 900 and 2,400 mg daily for both AEDs. In the other two studies, OXC and PHT dosages were 450 to 2,400 mg daily and 150 to 800 mg daily, respectively.
In the OXC versus VPA study, 249 patients aged 15 to 65 years were randomized. The groups were well matched with respect to age, sex, seizure type, and duration of epilepsy. Nearly 62% of the patients had partial seizures as their predominant seizure type; the others had generalized seizures without focal onset. Although this was a study of newly diagnosed patients, the mean duration of epilepsy was approximately 180 weeks.
In the adult OXC versus PHT study, 287 patients aged 15 to 91 years were randomized. The treatment groups were well matched. Most patients (63%) had partial seizures as their main seizure type (59% of OXC- and 68% of PHT-treated patients); the rest had generalized seizures without partial onset. The mean duration of epilepsy was 95 and 89 weeks for the OXC- and PHT-treated patients, respectively. Patients were previously untreated for their seizures.
In the pediatric OXC versus PHT study, 193 patients aged 5 to 17 years were randomized. The treatment groups were well matched. Most patients (78%) had partial seizures as their main seizure type; the rest had generalized seizures without
partial onset. The mean duration of epilepsy was 30 and 38 weeks for the OXC- and PHT-treated patients, respectively. Patients were previously untreated for their seizures.
TABLE 47.1. LARGE CONTROLLED CLINICAL TRIALS OF OXCARBAZEPINE
In each of these studies, the primary efficacy variable was the proportion of seizure-free patients who had at least one seizure assessment during the maintenance period (Table 47.3). Efficacy was evaluated during a 48-week maintenance period.
In the OXC versus VPA study, 212 patients (85% of those randomized) were included in the efficacy analysis. Slightly more than half of the patients in each treatment group remained seizure free during the maintenance period; there was no statistically significant treatment difference. Similarly, there was no treatment difference in the percentage of patients with partial-onset seizures who were seizure free (46% and 48% for OXC and VPA, respectively) or the proportion of patients with primary generalized seizures who were seizure free (72% and 62%, respectively). A greater proportion of VPA-treated patients with secondarily generalized seizures as their main seizure type were seizure free compared with OXC-treated patients, although the number of patients in each treatment arm was low. Six patients in each treatment group discontinued treatment prematurely because of lack of efficacy.
TABLE 47.2. MONOTHERAPY DOUBLE-BLIND COMPARATIVE TRIALS IN NEWLY TREATED PATIENTS.
TABLE 47.3. MONOTHERAPY DOUBLE-BLIND COMPARATIVE TRIALS IN NEWLY TREATED PATIENTS: SEIZURE-FREE RATES FOR THE 48-WEEK TREATMENT PERIOD
In the adult OXC versus PHT study, 237 patients (83% of those randomized) were included in the efficacy analysis. Overall, nearly 60% of patients in each treatment group were seizure free during the maintenance period; there was no statistically significant treatment difference. Similarly, there was no treatment difference in the percentage of patients with partial-onset seizures who were seizure free (56% and 53% for OXC and PHT, respectively) or the proportion of patients with primary generalized seizures who were seizure free (64% and 68%, respectively). One patient in each treatment group discontinued treatment prematurely because of lack of efficacy.
In the pediatric OXC versus PHT study, 158 patients (82% of those randomized) were included in the efficacy analysis. Nearly 60% of patients in each treatment group were seizure free during the maintenance period; there was no statistically significant treatment difference. Similarly, there was no treatment difference in the percentage of patients with partial-onset seizures who were seizure free (60% and 62% for OXC and PHT, respectively) or the proportion of patients with primary generalized seizures who were seizure free (59% and 54%, respectively). Four OXCand three PHT-treated patients discontinued treatment prematurely because of lack of efficacy.
Although informative clinically, these comparative monotherapy studies lacked true control groups. This problem was addressed by another monotherapy trial design, the inpatient presurgical design (8). An impressive degree of seizure reduction was seen in an open-label pilot trial of OXC monotherapy in presurgical patients (9); therefore, a placebo-controlled trial of OXC monotherapy was performed (10), the first placebo-controlled trial of OXC (Figure 47.1). This multicenter, double-blind, randomized, two-arm, parallel monotherapy trial compared OXC 1,200 mg twice daily with placebo in inpatients with refractory partial seizures who had undergone complete taper-off of
AEDs and completed a presurgical evaluation. Patients exited the trial after completing the 10-day treatment period or after experiencing four partial seizures, two new-onset secondarily generalized seizures, serial seizures, or status epilepticus, whichever came first.
FIGURE 47.1. Oxcarbazepine (OXC) monotherapy inpatient presurgical study design. (From Schachter SC, Vazquez B, Fisher RS, et al. Oxcarbazepine: double-blind, randomized, placebo-control, monotherapy trial for partial seizures. Neurology 1999;52: 732-737, with permission.)
One hundred two patients were randomized at 10 sites. The 56 men and 46 women were from 11 to 62 years of age and had an average of 4.6 partial seizures during a 48-hour period before randomization. Therapeutic dosages of OXC were reached with a 24-hour titration scheme. The primary efficacy variable, time to meeting one of the exit criteria, was statistically significant in favor of OXC (p = .0001; Figure 47.2). The secondary efficacy variables, percentage of patients who met one of the exit criteria and total partial seizure frequency from the 2nd through 10th day of doubleblind treatment, also were statistically significant in favor of OXC. Thirteen of the 51 OXC-treated patients (25%) remained seizure free throughout the entire 10-day treatment period, compared with only 1 placebo-treated patient (2%).
Two outpatient, double-blind OXC monotherapy studies compared seizure frequencies in patients with medically refractory partial epilepsy (11,12). In both studies, one group of patients was randomized to OXC 2,400 mg/day and the other group was randomized to tapering dosages of OXC down to 300 mg/day. The primary efficacy outcome in both studies was time to meeting one of four exit criteria: twofold increase in partial seizure frequency in any 28day treatment period relative to baseline; a twofold increase in the highest consecutive 2-day partial seizure frequency relative to baseline; occurrence of a single generalized seizure if none occurred in the previous 6 months; or prolongation or worsening of seizures requiring intervention. In each study, there was a significant difference in time to exit in favor of the high-dose OXC group.
FIGURE 47.2. Oxcarbazepine (OXC) monotherapy inpatient presurgical study. Time to exit: OXC vs. placebo. Day 0 = first day of full-dose (1,200 mg/day) treatment. Schachter SC, Vazquez B, Fisher RS, et al. Oxcarbazepine: double-blind, randomized, placebo-control, monotherapy trial for partial seizures. Neurology 1999;52:732-737, with permission.
Add-on Trials; Open-Label, Long-Term Trials; and Retrospective Studies
A double-blind, randomized, crossover study compared OXC with CBZ as add-on therapy in 48 institutionalized patients with refractory epilepsy (13). The mean daily doses of OXC and CBZ were 2,628 mg and 1,302 mg, respectively. Patients with tonic-clonic or clonic seizures had significantly fewer seizures when treated with OXC compared with CBZ, although no significant treatment differences were seen in frequencies of partial or myoclonic seizures. Serum concentrations of concomitant AEDs were not controlled; PHT and VPA concentrations were higher during OXC treatment compared with CBZ and could have contributed to the treatment effect. Another crossover study
compared OXC with CBZ as add-on therapy in 16 patients with at least one seizure per month and found 90% reduction in seizure frequency for both treatment groups (14).
TABLE 47.4. ADULT ADD-ON OXCARBAZEPINE STUDY: INTENT-TO-TREAT RESPONSE
Van Parys and Meinardi treated 260 patients with open-label OXC for a total of 935 patient-years of exposure (15). Among 89 patients whose treatment was changed to OXC because CBZ treatment had been ineffective, 8 (9%) became seizure free and 36 others (40%) showed substantial improvement in seizure frequency.
A double-blind, multicenter, randomized, placebo-controlled trial assessed the efficacy and safety of three different doses of adjunctive OXC (600, 1,200, and 2,400 mg/day) compared with placebo in adults with medically refractory partial seizures (16) (Table 47.4). Nearly three-fourths of the enrolled patients were taking CBZ as a concomitant AED. The primary efficacy variable was percentage change in seizure frequency per 28 days relative to baseline. The median reduction in seizure frequency was 26%, 40%, 50%, and 8% for patients receiving 600, 1,200, or 2,400 mg/day OXC or placebo, respectively (all OXC groups p < .0001). Further, among patients in the 600-, 1,200-, or 2,400-mg/day OXC groups, 27%, 42%, and 50%, respectively, had >50% reduction in seizure frequency compared with 13% for placebo (all p < .001). A separate analysis of patients who took concomitant CBZ showed percentage reductions in seizure frequency of 22%, 40%, and 50% for 600, 1,200, and 2,400 mg/day OXC, respectively. These findings suggest that the addition of OXC to maximally tolerated dosages of CBZ is as likely to result in seizure improvement as the addition of OXC to regimens not containing CBZ.
A double-blind, multicenter, randomized, placebo-controlled trial assessed the efficacy and safety of adjunctive OXC (6 to 50 mg/kg/day) versus placebo in children aged 3 to 17 years with partial seizures refractory to other AEDs (17). In approximately half the enrolled patients, CBZ was a concomitant AED. OXC-treated patients (n = 138) experienced a 35% median reduction from baseline in partial seizure frequency, compared with 9% for placebo-treated patients (n = 129; p = .0001). Further, 41% of patients treated with OXC had at least a 50% reduction in partial seizure frequency compared with baseline versus 22% of placebo-treated patient (p = .0005). Five OXC-treated patients and one patient on placebo were seizure free during the 98-day double-blind treatment period. The efficacy of the combination of CBZ and OXC was not reported or compared with combinations of OXC with other AEDs
Two retrospective open studies evaluated the effectiveness of OXC in children (18,19). Borusiak et al. assessed the efficacy of OXC as monotherapy or add-on therapy in 46 children (mean age, 10.3 years; mean duration of epilepsy, 7.2 years) (18). The mean dose of OXC during chronic treatment was 56.7 mg/kg/day. Twelve children discontinued OXC because of insufficient seizure control. Among those children remaining on treatment for 1 year, 19 had at least 50% reduction in seizure frequency and 4 were seizure free.
In the other study, chart analysis of 53 children younger than 7 years of age with seizures refractory to one or more AEDs showed that young children needed a higher dose per body weight of OXC than adults: the mean maximum OXC dose was 50 mg/kg/day (range, 21 to 86 mg/kg/day) (19). Twelve of 44 (27%) children with localization-related epilepsy became seizure free and an additional 16 (36%) had at least 50% seizure reduction. None of the children with generalized epilepsy became seizure free.
DOSAGE AND ADMINISTRATION
OXC is available as 300- and 600-mg scored tablets and can be taken with or without food. The recommended dosage as monotherapy in adults is 600 to 1,200 mg/day in two divided doses; higher dosages may be necessary when used as polytherapy in patients with refractory seizures. Adult patients with new-onset seizures can be initiated at 150 mg/day; the dosage can be increased by 150 mg every 2 to 4 days until the target dose is reached. Higher starting doses and faster titration rates are feasible in selected patients, although dose-related neurotoxicity may limit the titration rates in some patients. Children should be initiated at 8 to 10 mg/kg/day; dosages can be increased weekly by 8 to 10 mg/kg/day to clinical effect.
In clinical practice, OXC often is substituted for CBZ. Dam suggests that the full maintenance dose of OXC (at 1.5 times the CBZ dose, somewhat less in the elderly) be started as CBZ is abruptly discontinued (20). Others have advocated a slower transition strategy by starting OXC at
low dose, with graduated increments as tolerated while CBZ is slowly tapered (21). OXC dosage reductions may be necessary once enzyme-inducing AEDs are fully discontinued if signs or symptoms of neurotoxicity develop.
There is a linear relationship between daily OXC dose and serum concentrations of the active metabolite (MHD) (22). However, the correlation between MHD concentrations and likelihood of efficacy varies widely among patients; therefore, the principal uses for MHD assays are to verify compliance and establish the therapeutic MHD concentration for individual patients.
REGULATORY STATUS AND INDICATIONS
OXC was synthesized in 1963 and first marketed in Denmark, Argentina, and Mexico in 1990. OXC now is registered in over 60 countries worldwide under the brand name Trileptal (Novartis, Summit, NJ) as monotherapy and add-on treatment for partial seizures with or without secondary generalized seizures and primary generalized tonic-clonic seizures. The U.S. Food and Drug Administration cleared OXC for marketing in the United States in February 2000 for use as monotherapy or adjunctive therapy in the treatment of partial seizures (simple partial, complex partial, secondarily generalized) in adults with epilepsy and as adjunctive therapy in the treatment of partial seizures in children 4 to 16 years of age with epilepsy.
The patient exposure currently is estimated to exceed 250,000 patients and 200,000 patient-years based on drug sales and an assumed average daily dose of 1,200 mg.
Despite their structural similarities, OXC and CBZ exhibit many differences and should be considered as distinct drugs. The chemical structures, pharmacokinetics, and metabolic pathways of their active metabolites are different; and their drug-drug interactions, side effect profiles, effects on laboratory values, and titration and dosing are distinctly different. Although their overall efficacy profiles are similar, seizures in some patients respond to one drug and not the other in controlled trials and open clinical experience. Hence, patients with partial-onset seizures that are refractory to CBZ may benefit from a trial of OXC, and vice-versa.
OXC shows comparable efficacy to PHT and VPA in addition to CBZ as monotherapy for partial-onset seizures. Adjunctive OXC affords incremental seizure control that is dose dependent, even for patients whose other AEDs include CBZ or whose seizures failed to respond to CBZ in the past.
Physicians will be reassured by the extensive previous clinical experience with this compound and unusually broad portfolio of clinical studies. OXC is an important treatment option for patients with epilepsy that should be considered first-line therapy for partial-onset seizures. Because only a limited number of intravenous AEDs are available, studies of the feasibility and efficacy of an intravenous formulation of MHD are warranted.